Systemic lupus erythematosus (SLE) is a devastating autoimmune disease that most commonly affects women in their child-bearing years. SLE attacks multiple organ systems, but renal and neurologic involvement are the usual harbingers of poor outcome. Despite effective, albeit toxic, immunosuppressive therapy, only 50% of patients with these serious manifestations will be alive 20 years after diagnosis. SLE remains a disease in critical need of better and safer interventions. VISTA (V-region Immunoglobulin-containing Suppressor of T cell Activation) is a novel, structurally distinct, Ig-superfamily negative checkpoint regulator whose closest phylogenetic relative is PD-L1. Like PD- L1, VISTA profoundly suppresses immunity, and blocking VISTA enables the development of therapeutic immunity to cancer in mouse models. We now demonstrate that a VISTA-Immunoglobulin fusion protein (VISTA-Ig), a VISTA pathway agonist, renders T cells unresponsive in vitro and is effective when administered in vivo early and late in murine models of SLE (NZBWF1 and NZM2410) and multiple sclerosis (EAE). VISTA- Ig is one of the first members of a new, promising class of drugs, negative checkpoint regulator pathway agonists, that actively and potently suppress immunity, and as such, may play an unprecedented role in the safe and effective treatment of SLE. Importantly, the VISTA-Ig effect is at the level of organ damage, and onset of action is immediate, with inhibition of T cell activation in <10 minutes of engagement of the putative receptor in vitro, and an abrupt reversal of proteinuria in mice within days in vivo. These properties predict a highly desirable rapid clinical response, potential synergy with slower onset B cell targeted therapies, and possibly a major, early steroid-sparing effect. This STTR proposal defines our strategy for advancing the translation of VISTA-Ig from a dramatically effective agent in murine SLE to a legitimate candidate for clinical trials in human SLE. These Phase II studies will continue to optimize both murine and human VISTA-Ig reagents in terms of the need for FcR-binding, potency, half-life, and immunogenicity, using a number of bioengineering techniques, both in vivo in murine SLE models and in vitro in studies of PBMC from non-human primates (NHPs), human controls and SLE patients. While doing so, we will further elucidate the mechanism of action of VISTA-Ig. Based on these studies, a lead candidate hVISTA-Ig will be produced in sufficient quantity and quality to move onto critical safety studies in non-human primates. ImmuNext has a successful track record of commercializing immunotherapies from SBIR projects, and we have assembled in very deliberate fashion a top-notch team of scientists and clinicians to bring this SLE translational project to fruition.